Telomere Metabolism and DNA Damage Response

  • Tej K. PanditaEmail author


Genomic stability is maintained by telomeres, the end terminal DNA protein structures that protect chromosomes from fusion or degradation. Telomeres are essential for the proper maintenance of chromosomes and may play a role in aging, cancer and several other diseases. Shortening or loss of telomeric DNA repeats or altered telomere chromatin structure is correlated with telomere dysfunction such as chromosome end-to-end associations/telomere fusions that could lead to gene amplification and genomic instability. The DNA structure at the end of telomeres is distinguished from DNA double strand breaks (DSBs) in order to avoid nonhomologous end-joining (NHEJ), which requires unique, higher order nucleoprotein structure. Telomeres are attached to the nuclear matrix and have a specific chromatin structure. Whether this special structure is maintained by specific chromatin changes is yet to be thoroughly investigated. Altered telomere chromatin structure has been linked to defective DNA damage response (DDR), and eukaryotic cells utilize the DDR mechanisms of proficient DNA repair and cell cycle checkpoints in order to maintain genomic stability. Studies of the DNA damage response has lead to the identification of sensors and transducers which constitute a hierarchical signaling paradigm for the transduction of the initial damage signal to numerous downstream effectors, some of which have a role in both genomic stability and telomere metabolism. This review will summarize the factors involved in telomere maintenance and the influence of such factors on the DNA damage response.


Telomere structure DDR Chromatin modifications Histone code ATM 



The work in my laboratory is supported by National Institute of Health grants CA129537 and CA123232 (T.K.P). We thank the members of my laboratory Q. Yang and S. Scott for their help and thoughtful discussion.


  1. 1.
    Pisano S, Galati A, Cacchione S. Telomeric nucleosomes: Forgotten players at chromosome ends. Cell Mol Life Sci 2008;65:3553–3563.Google Scholar
  2. 2.
    de Lange T. Shelterin: the protein complex that shapes and safeguards human telomeres. Genes Dev 2005;19:2100–10.PubMedGoogle Scholar
  3. 3.
    Griffith JD, Comeau L, Rosenfield S, et al. Mammalian telomeres end in a large duplex loop. Cell 1999;97:503–14.PubMedGoogle Scholar
  4. 4.
    Stansel RM, de Lange T, Griffith JD. T-loop assembly in vitro involves binding of TRF2 near the 3' telomeric overhang. EMBO J 2001;20:5532–40.PubMedGoogle Scholar
  5. 5.
    Celli GB, de Lange T. DNA processing is not required for ATM-mediated telomere damage response after TRF2 deletion. Nat Cell Biol 2005;7:712–8.PubMedGoogle Scholar
  6. 6.
    Zhu XD, Niedernhofer L, Kuster B, Mann M, Hoeijmakers JH, de Lange T. ERCC1/XPF removes the 3' overhang from uncapped telomeres and represses formation of telomeric DNA-containing double minute chromosomes. Mol Cell 2003;12:1489–98.PubMedGoogle Scholar
  7. 7.
    Konishi A, de Lange T. Cell cycle control of telomere protection and NHEJ revealed by a ts mutation in the DNA-binding domain of TRF2. Genes Dev 2008;22:1221–30.PubMedGoogle Scholar
  8. 8.
    Karlseder J, Broccoli D, Dai Y, Hardy S, de Lange T. p53- and ATM-dependent apoptosis induced by telomeres lacking TRF2. Science 1999;283:1321–5.PubMedGoogle Scholar
  9. 9.
    Karlseder J, Smogorzewska A, de Lange T. Senescence induced by altered telomere state, not telomere loss. Science 2002;295:2446–9.PubMedGoogle Scholar
  10. 10.
    Dimitrova N, de Lange T. MDC1 accelerates nonhomologous end-joining of dysfunctional telomeres. Genes Dev 2006;20:3238–43.PubMedGoogle Scholar
  11. 11.
    De Lange T. Telomere-related genome instability in cancer. Cold Spring Harb Symp Quant Biol 2005;70:197–204.PubMedGoogle Scholar
  12. 12.
    Baumann P, Cech TR. Pot1, the putative telomere end-binding protein in fission yeast and humans. Science 2001;292:1171–5.PubMedGoogle Scholar
  13. 13.
    Blackburn EH. Switching and signaling at the telomere. Cell 2001;106:661–73.PubMedGoogle Scholar
  14. 14.
    de Lange T. Protection of mammalian telomeres. Oncogene 2002;21:532–40.PubMedGoogle Scholar
  15. 15.
    Gottschling DE, Cech TR. Chromatin structure of the molecular ends of Oxytricha macronuclear DNA: phased nucleosomes and a telomeric complex. Cell 1984;38:501–10.PubMedGoogle Scholar
  16. 16.
    Horvath MP, Schweiker VL, Bevilacqua JM, Ruggles JA, Schultz SC. Crystal structure of the Oxytricha nova telomere end binding protein complexed with single strand DNA. Cell 1998;95:963–74.PubMedGoogle Scholar
  17. 17.
    Pennock E, Buckley K, Lundblad V. Cdc13 delivers separate complexes to the telomere for end protection and replication. Cell 2001;104:387–96.PubMedGoogle Scholar
  18. 18.
    Grandin N, Damon C, Charbonneau M. Ten1 functions in telomere end protection and length regulation in association with Stn1 and Cdc13. EMBO J 2001;20:1173–83.PubMedGoogle Scholar
  19. 19.
    Lei M, Podell ER, Baumann P, Cech TR. DNA self-recognition in the structure of Pot1 bound to telomeric single-stranded DNA. Nature 2003;426:198–203.PubMedGoogle Scholar
  20. 20.
    Yang Q, Zheng YL, Harris CC. POT1 and TRF2 cooperate to maintain telomeric integrity. Mol Cell Biol 2005;25:1070–80.PubMedGoogle Scholar
  21. 21.
    Hockemeyer D, Sfeir AJ, Shay JW, Wright WE, de Lange T. POT1 protects telomeres from a transient DNA damage response and determines how human chromosomes end. Embo J 2005;24:2667–78.PubMedGoogle Scholar
  22. 22.
    Opresko PL, Mason PA, Podell ER, et al. POT1 stimulates RecQ helicases WRN and BLM to unwind telomeric DNA substrates. J Biol Chem 2005;280:32069–80.PubMedGoogle Scholar
  23. 23.
    Wang X, Liu L, Montagna C, Ried T, Deng CX. Haploinsufficiency of Parp1 accelerates Brca1-associated centrosome amplification, telomere shortening, genetic instability, apoptosis, and embryonic lethality. Cell Death Differ 2007;14:924–31.PubMedGoogle Scholar
  24. 24.
    Loayza D, De Lange T. POT1 as a terminal transducer of TRF1 telomere length control. Nature 2003;423:1013–8.PubMedGoogle Scholar
  25. 25.
    Veldman T, Etheridge KT, Counter CM. Loss of hPot1 function leads to telomere instability and a cut-like phenotype. Curr Biol 2004;14:2264–70.PubMedGoogle Scholar
  26. 26.
    Wu L, Multani AS, He H, et al. Pot1 deficiency initiates DNA damage checkpoint activation and aberrant homologous recombination at telomeres. Cell 2006;126:49–62.PubMedGoogle Scholar
  27. 27.
    Baumann P, Podell E, Cech TR. Human Pot1 (protection of telomeres) protein: cytolocalization, gene structure, and alternative splicing. Mol Cell Biol 2002;22:8079–87.PubMedGoogle Scholar
  28. 28.
    Yang Q, Zhang R, Horikawa I, et al. Functional diversity of human protection of telomeres 1 isoforms in telomere protection and cellular senescence. Cancer Res 2007;67:11677–86.PubMedGoogle Scholar
  29. 29.
    Wu P, de Lange T. No Overt Nucleosome Eviction at Deprotected Telomeres. Mol Cell Biol 2008.Google Scholar
  30. 30.
    Pandita TK, Hittelman WN. Initial chromosome damage but not DNA damage is greater in ataxia telangiectasia cells. Radiat Res 1992;130:94–103.PubMedGoogle Scholar
  31. 31.
    Sharma GG, Gupta A, Wang H, et al. hTERT associates with human telomeres and enhances genomic stability and DNA repair. Oncogene 2003;22:131–46.PubMedGoogle Scholar
  32. 32.
    Tahara H, Kusunoki M, Yamanaka Y, Matsumura S, Ide T. G-tail telomere HPA: simple measurement of human single-stranded telomeric overhangs. Nat Methods 2005;2:829–31.PubMedGoogle Scholar
  33. 33.
    Crabbe L, Verdun RE, Haggblom CI, Karlseder J. Defective telomere lagging strand synthesis in cells lacking WRN helicase activity. Science 2004;306:1951–3.PubMedGoogle Scholar
  34. 34.
    Maser RS, DePinho RA. Telomeres and the DNA damage response: why the fox is guarding the henhouse. DNA Repair (Amst) 2004;3:979–88.Google Scholar
  35. 35.
    Feldser DM, Hackett JA, Greider CW. Telomere dysfunction and the initiation of genome instability. Nat Rev Cancer 2003;3:623–7.PubMedGoogle Scholar
  36. 36.
    Pandita TK. ATM function and telomere stability. Oncogene 2002;21:611–8.PubMedGoogle Scholar
  37. 37.
    van Steensel B, Smogorzewska A, de Lange T. TRF2 protects human telomeres from end-to-end fusions. Cell 1998;92:401–13.PubMedGoogle Scholar
  38. 38.
    Karlseder J, Hoke K, Mirzoeva OK, et al. The Telomeric Protein TRF2 Binds the ATM Kinase and Can Inhibit the ATM-Dependent DNA Damage Response. PLoS Biol 2004;2:E240.PubMedGoogle Scholar
  39. 39.
    Gu B, Bessler M, Mason PJ. Dyskerin, telomerase and the DNA damage response. Cell Cycle 2009;8.Google Scholar
  40. 40.
    Takai H, Smogorzewska A, de Lange T. DNA damage foci at dysfunctional telomeres. Curr Biol 2003;13:1549–56.PubMedGoogle Scholar
  41. 41.
    Slijepcevic P. The role of DNA damage response proteins at telomeres – an "integrative" model. DNA Repair (Amst) 2006;5:1299–306.Google Scholar
  42. 42.
    Pandita TK, Pathak S, Geard CR. Chromosome end associations, telomeres and telomerase activity in ataxia telangiectasia cells. Cytogenet Cell Genet 1995;71:86–93.PubMedGoogle Scholar
  43. 43.
    Pandita TK, Hall EJ, Hei TK, et al. Chromosome end-to-end associations and telomerase activity during cancer progression in human cells after treatment with alpha-particles simulating radon progeny. Oncogene 1996;13:1423–30.PubMedGoogle Scholar
  44. 44.
    Pandita TK, Westphal CH, Anger M, et al. Atm inactivation results in aberrant telomere clustering during meiotic prophase. Mol Cell Biol 1999;19:5096–105.PubMedGoogle Scholar
  45. 45.
    Pandita TK, Dhar S. Influence of ATM function on interactions between telomeres and nuclear matrix. Radiat Res 2000;154:133–9.PubMedGoogle Scholar
  46. 46.
    Scherthan H, Jerratsch M, Dhar S, Wang YA, Goff SP, Pandita TK. Meiotic telomere distribution and Sertoli cell nuclear architecture are altered in Atm- and Atm-p53-deficient mice. Mol Cell Biol 2000;20:7773–83.PubMedGoogle Scholar
  47. 47.
    Pandita TK, Hunt CR, Sharma GG, Yang Q. Regulation of telomere movement by telomere chromatin structure. Cell Mol Life Sci 2007;64:131–8.PubMedGoogle Scholar
  48. 48.
    Pandita TK. The role of ATM in telomere structure and function. Radiat Res 2001;156:642–7.PubMedGoogle Scholar
  49. 49.
    Pandita TK. Telomeres and Telomerase Encyclopedia of Cancer 2002;4:335–362.Google Scholar
  50. 50.
    Pandita TK. A multifaceted role for ATM in genome maintenance. Exp Rev Mol Med 2003;5:1–21.Google Scholar
  51. 51.
    Gupta A, Guerin-Peyrou TG, Sharma GG, et al. The mammalian ortholog of Drosophila MOF that acetylates histone H4 lysine 16 is essential for embryogenesis and oncogenesis. Mol Cell Biol 2008;28:397–409.PubMedGoogle Scholar
  52. 52.
    Gupta A, Sharma GG, Young CS, et al. Involvement of human MOF in ATM function. Mol Cell Biol 2005;25:5292–305.PubMedGoogle Scholar
  53. 53.
    Sun Y, Jiang X, Chen S, Fernandes N, Price BD. A role for the Tip60 histone acetyltransferase in the acetylation and activation of ATM. Proc Natl Acad Sci USA 2005;102:13182–7.PubMedGoogle Scholar
  54. 54.
    Fischle W, Wang Y, Allis CD. Histone and chromatin cross-talk. Curr Opin Cell Biol 2003;15:172–83.PubMedGoogle Scholar
  55. 55.
    Legube G, Trouche D. Regulating histone acetyltransferases and deacetylases. EMBO Rep 2003;4:944–7.PubMedGoogle Scholar
  56. 56.
    Pruss D, Reeves R, Bushman FD, Wolffe AP. The influence of DNA and nucleosome structure on integration events directed by HIV integrase. J Biol Chem 1994;269:25031–41.PubMedGoogle Scholar
  57. 57.
    Pruss D, Bushman FD, Wolffe AP. Human immunodeficiency virus integrase directs integration to sites of severe DNA distortion within the nucleosome core. Proc Natl Acad Sci USA 1994;91:5913–7.PubMedGoogle Scholar
  58. 58.
    Otten AD, Tapscott SJ. Triplet repeat expansion in myotonic dystrophy alters the adjacent chromatin structure. Proc Natl Acad Sci USA 1995;92:5465–9.PubMedGoogle Scholar
  59. 59.
    Wallrath LL, Lu Q, Granok H, Elgin SC. Architectural variations of inducible eukaryotic promoters: preset and remodeling chromatin structures. Bioessays 1994;16:165–70.PubMedGoogle Scholar
  60. 60.
    Hoeijmakers JH. DNA repair mechanisms. Maturitas 2001;38:17–22; discussion -3.PubMedGoogle Scholar
  61. 61.
    Fernandez-Capetillo O, Mahadevaiah SK, Celeste A, et al. H2AX is required for chromatin remodeling and inactivation of sex chromosomes in male mouse meiosis. Dev Cell 2003;4:497–508.PubMedGoogle Scholar
  62. 62.
    Fernandez-Capetillo O, Nussenzweig A. Linking histone deacetylation with the repair of DNA breaks. Proc Natl Acad Sci USA 2004;101:1427–8.PubMedGoogle Scholar
  63. 63.
    Nakamura TM, Du LL, Redon C, Russell P. Histone H2A phosphorylation controls Crb2 recruitment at DNA breaks, maintains checkpoint arrest, and influences DNA repair in fission yeast. Mol Cell Biol 2004;24:6215–30.PubMedGoogle Scholar
  64. 64.
    Sims RJ, 3rd, Nishioka K, Reinberg D. Histone lysine methylation: a signature for chromatin function. Trends Genet 2003;19:629–39.PubMedGoogle Scholar
  65. 65.
    Olins DE, Olins AL. Chromatin history: our view from the bridge. Nat Rev Mol Cell Biol 2003;4:809–14.PubMedGoogle Scholar
  66. 66.
    Workman JL, Kingston RE. Alteration of nucleosome structure as a mechanism of transcriptional regulation. Annu Rev Biochem 1998;67:545–79.PubMedGoogle Scholar
  67. 67.
    Strahl BD, Grant PA, Briggs SD, et al. Set2 is a nucleosomal histone H3-selective methyltransferase that mediates transcriptional repression. Mol Cell Biol 2002;22:1298–306.PubMedGoogle Scholar
  68. 68.
    Khorasanizadeh S. The nucleosome: from genomic organization to genomic regulation. Cell 2004;116:259–72.PubMedGoogle Scholar
  69. 69.
    Green CM, Almouzni G. When repair meets chromatin. First in series on chromatin dynamics. EMBO Rep 2002;3:28–33.PubMedGoogle Scholar
  70. 70.
    Vidanes GM, Bonilla CY, Toczyski DP. Complicated tails: histone modifications and the DNA damage response. Cell 2005;121:973–6.PubMedGoogle Scholar
  71. 71.
    Peterson CL, Cote J. Cellular machineries for chromosomal DNA repair. Genes Dev 2004;18:602–16.PubMedGoogle Scholar
  72. 72.
    van Attikum H, Gasser SM. The histone code at DNA breaks: a guide to repair? Nat Rev Mol Cell Biol 2005;6:757–65.PubMedGoogle Scholar
  73. 73.
    Lydall D, Whitehall S. Chromatin and the DNA damage response. DNA Repair (Amst) 2005;4:1195–207.Google Scholar
  74. 74.
    Wurtele H, Verreault A. Histone post-translational modifications and the response to DNA double-strand breaks. Curr Opin Cell Biol 2006;18:137–44.PubMedGoogle Scholar
  75. 75.
    Loizou JI, Murr R, Finkbeiner MG, Sawan C, Wang ZQ, Herceg Z. Epigenetic information in chromatin: the code of entry for DNA repair. Cell Cycle 2006;5:696–701.PubMedGoogle Scholar
  76. 76.
    Lund AH, van Lohuizen M. Epigenetics and cancer. Genes Dev 2004;18:2315–35.PubMedGoogle Scholar
  77. 77.
    Aucott R, Bullwinkel, J., Yu, Y., Shi, W., Billur, M., Brown, J.P., Menzel, U., Kioussis, D., Wang, G., Reisert, I., Weimer, J., Pandita, R.K., Sharma, G.G., Pandita, T.K., Fundele R, Singh P.B. HP1? is required for development of the cerebral neocortex and diaphragmatic neuromuscular junctions. J Cell Biol 2008;183:597–606.Google Scholar
  78. 78.
    Lavin MF, Kozlov S. ATM activation and DNA damage response. Cell Cycle 2007;6:931–42.PubMedGoogle Scholar
  79. 79.
    Bentley NJ, Holtzman DA, Flaggs G, et al. The Schizosaccharomyces pombe rad3 checkpoint gene. Embo J 1996;15:6641–51.PubMedGoogle Scholar
  80. 80.
    Lydall D, Nikolsky Y, Bishop DK, Weinert T. A meiotic recombination checkpoint controlled by mitotic checkpoint genes. Nature 1996;383:840–3.PubMedGoogle Scholar
  81. 81.
    Keith CT, Schreiber SL. PIK-related kinases: DNA repair, recombination, and cell cycle checkpoints. Science 1995;270:50–1.PubMedGoogle Scholar
  82. 82.
    Savitsky K, Bar-Shira A, Gilad S, et al. A single ataxia telangiectasia gene with a product similar to PI-3 kinase. Science 1995;268:1749–53.PubMedGoogle Scholar
  83. 83.
    Pandita TK, Hittelman WN. The contribution of DNA and chromosome repair deficiencies to the radiosensitivity of ataxia-telangiectasia. Radiat Res 1992;131:214–23.PubMedGoogle Scholar
  84. 84.
    Morgan SE, Lovly C, Pandita TK, Shiloh Y, Kastan MB. Fragments of ATM which have dominant-negative or complementing activity. Mol Cell Biol 1997;17:2020–9.PubMedGoogle Scholar
  85. 85.
    Barlow C, Hirotsune S, Paylor R, et al. Atm-deficient mice: a paradigm of ataxia telangiectasia. Cell 1996;86:159–71.PubMedGoogle Scholar
  86. 86.
    Elson A, Wang Y, Daugherty CJ, et al. Pleiotropic defects in ataxia-telangiectasia protein-deficient mice. Proc Natl Acad Sci USA 1996;93:13084–9.PubMedGoogle Scholar
  87. 87.
    Xu Y, Ashley T, Brainerd EE, Bronson RT, Meyn MS, Baltimore D. Targeted disruption of ATM leads to growth retardation, chromosomal fragmentation during meiosis, immune defects, and thymic lymphoma. Genes Dev 1996;10:2411–22.PubMedGoogle Scholar
  88. 88.
    Bakkenist CJ, Kastan MB. DNA damage activates ATM through intermolecular autophosphorylation and dimer dissociation. Nature 2003;421:499–506.PubMedGoogle Scholar
  89. 89.
    Kozlov SV, Graham ME, Peng C, Chen P, Robinson PJ, Lavin MF. Involvement of novel autophosphorylation sites in ATM activation. EMBO J 2006;25:3504–14.PubMedGoogle Scholar
  90. 90.
    Lee JH, Paull TT. Direct activation of the ATM protein kinase by the Mre11/Rad50/Nbs1 complex. Science 2004;304:93–6.PubMedGoogle Scholar
  91. 91.
    Bredemeyer AL, Sharma GG, Huang CY, et al. ATM stabilizes DNA double-strand-break complexes during V(D)J recombination. Nature 2006;442:466–70.PubMedGoogle Scholar
  92. 92.
    Huang CY, Sharma GG, Walker LM, Bassing CH, Pandita TK, Sleckman BP. Defects in coding joint formation in vivo in developing ATM-deficient B and T lymphocytes. J Exp Med 2007;204:1371–81.PubMedGoogle Scholar
  93. 93.
    Callen E, Jankovic M, Difilippantonio S, et al. ATM prevents the persistence and propagation of chromosome breaks in lymphocytes. Cell 2007;130:63–75.PubMedGoogle Scholar
  94. 94.
    Richard DJ, Bolderson E, Cubeddu L, et al. Single-stranded DNA-binding protein hSSB1 is critical for genomic stability. Nature 2008;453:677–81.PubMedGoogle Scholar
  95. 95.
    Usui T, Ogawa H, Petrini JH. A DNA damage response pathway controlled by Tel1 and the Mre11 complex. Mol Cell 2001;7:1255–66.PubMedGoogle Scholar
  96. 96.
    Chan SW, Chang J, Prescott J, Blackburn EH. Altering telomere structure allows telomerase to act in yeast lacking ATM kinases. Curr Biol 2001;11:1240–50.PubMedGoogle Scholar
  97. 97.
    Stohr BA, Blackburn EH. ATM mediates cytotoxicity of a mutant telomerase RNA in human cancer cells. Cancer Res 2008;68:5309–17.PubMedGoogle Scholar
  98. 98.
    Gately DP, Hittle JC, Chan GK, Yen TJ. Characterization of ATM expression, localization, and associated DNA-dependent protein kinase activity. Mol Biol Cell 1998;9:2361–74.PubMedGoogle Scholar
  99. 99.
    Andegeko Y, Moyal L, Mittelman L, Tsarfaty I, Shiloh Y, Rotman G. Nuclear retention of ATM at sites of DNA double strand breaks. J Biol Chem 2001;276:38224–30.PubMedGoogle Scholar
  100. 100.
    Kishi S, Lu KP. A critical role for Pin2/TRF1 in ATM-dependent regulation. Inhibition of Pin2/TRF1 function complements telomere shortening, radiosensitivity, and the G(2)/M checkpoint defect of ataxia-telangiectasia cells. J Biol Chem 2002;277:7420–9.PubMedGoogle Scholar
  101. 101.
    Kishi S, Zhou XZ, Ziv Y, et al. Telomeric protein Pin2/TRF1 as an important ATM target in response to double strand DNA breaks. J Biol Chem 2001;276:29282–91.PubMedGoogle Scholar
  102. 102.
    Smilenov LB, Dhar S, Pandita TK. Altered telomere nuclear matrix interactions and nucleosomal periodicity in ataxia telangiectasia cells before and after ionizing radiation treatment. Mol Cell Biol 1999;19:6963–71.PubMedGoogle Scholar
  103. 103.
    Takata H, Kanoh Y, Gunge N, Shirahige K, Matsuura A. Reciprocal association of the budding yeast ATM-related proteins Tel1 and Mec1 with telomeres in vivo. Mol Cell 2004;14:515–22.PubMedGoogle Scholar
  104. 104.
    Verdun RE, Crabbe L, Haggblom C, Karlseder J. Functional human telomeres are recognized as DNA damage in G2 of the cell cycle. Mol Cell 2005;20:551–61.PubMedGoogle Scholar
  105. 105.
    Baskaran R, Wood LD, Whitaker LL, et al. Ataxia telangiectasia mutant protein activates c-Abl tyrosine kinase in response to ionizing radiation. Nature 1997;387:516–9.PubMedGoogle Scholar
  106. 106.
    Shafman T, Khanna KK, Kedar P, et al. Interaction between ATM protein and c-Abl in response to DNA damage. Nature 1997;387:520–3.PubMedGoogle Scholar
  107. 107.
    Kharbanda S, Kumar V, Dhar S, et al. Regulation of the hTERT telomerase catalytic subunit by the c-Abl tyrosine kinase. Curr Biol 2000;10:568–75.PubMedGoogle Scholar
  108. 108.
    Lieberman HB, Hopkins KM, Nass M, Demetrick D, Davey S. A human homolog of the Schizosaccharomyces pombe rad9+ checkpoint control gene. Proc Natl Acad Sci USA 1996;93:13890–5.PubMedGoogle Scholar
  109. 109.
    Chen MJ, Lin YT, Lieberman HB, Chen G, Lee EY. ATM-dependent phosphorylation of human Rad9 is required for ionizing radiation-induced checkpoint activation. J Biol Chem 2001;276:16580–6.PubMedGoogle Scholar
  110. 110.
    St Onge RP, Udell CM, Casselman R, Davey S. The human G2 checkpoint control protein hRAD9 is a nuclear phosphoprotein that forms complexes with hRAD1 and hHUS1. Mol Biol Cell 1999;10:1985–95.PubMedGoogle Scholar
  111. 111.
    Venclovas C, Thelen MP. Structure-based predictions of Rad1, Rad9, Hus1 and Rad17 participation in sliding clamp and clamp-loading complexes. Nucleic Acids Res 2000;28:2481–93.PubMedGoogle Scholar
  112. 112.
    Greer DA, Besley BD, Kennedy KB, Davey S. hRad9 rapidly binds DNA containing double-strand breaks and is required for damage-dependent topoisomerase II beta binding protein 1 focus formation. Cancer Res 2003;63:4829–35.PubMedGoogle Scholar
  113. 113.
    Pandita RK, Sharma GG, Laszlo A, et al. Mammalian rad9 plays a role in telomere stability, s- and g2-phase-specific cell survival, and homologous recombinational repair. Mol Cell Biol 2006;26:1850–64.PubMedGoogle Scholar
  114. 114.
    Hamer G, Roepers-Gajadien HL, van Duyn-Goedhart A, et al. DNA double-strand breaks and gamma-H2AX signaling in the testis. Biol Reprod 2003;68:628–34.PubMedGoogle Scholar
  115. 115.
    Gilley D, Tanaka H, Hande MP, et al. DNA-PKcs is critical for telomere capping. Proc Natl Acad Sci USA 2001;98:15084–8.PubMedGoogle Scholar
  116. 116.
    Taccioli GE, Gottlieb TM, Blunt T, et al. Ku80: product of the XRCC5 gene and its role in DNA repair and V(D)J recombination. Science 1994;265:1442–5.PubMedGoogle Scholar
  117. 117.
    Critchlow SE, Jackson SP. DNA end-joining: from yeast to man. Trends Biochem Sci 1998;23:394–8.PubMedGoogle Scholar
  118. 118.
    Kanaar R, Hoeijmakers JH, van Gent DC. Molecular mechanisms of DNA double strand break repair. Trends Cell Biol 1998;8:483–9.PubMedGoogle Scholar
  119. 119.
    Giffin W, Torrance H, Rodda DJ, Prefontaine GG, Pope L, Hache RJ. Sequence-specific DNA binding by Ku autoantigen and its effects on transcription. Nature 1996;380:265–8.PubMedGoogle Scholar
  120. 120.
    Ludwig DL, Chen F, Peterson SR, Nussenzweig A, Li GC, Chen DJ. Ku80 gene expression is Sp1-dependent and sensitive to CpG methylation within a novel cis element. Gene 1997;199:181–94.PubMedGoogle Scholar
  121. 121.
    Galande S, Kohwi-Shigematsu T. Poly(ADP-ribose) polymerase and Ku autoantigen form a complex and synergistically bind to matrix attachment sequences. J Biol Chem 1999;274:20521–8.PubMedGoogle Scholar
  122. 122.
    Nussenzweig A, Chen C, da Costa Soares V, et al. Requirement for Ku80 in growth and immunoglobulin V(D)J recombination. Nature 1996;382:551–5.PubMedGoogle Scholar
  123. 123.
    Boulton SJ, Jackson SP. Identification of a Saccharomyces cerevisiae Ku80 homologue: roles in DNA double strand break rejoining and in telomeric maintenance. Nucleic Acids Res 1996;24:4639–48.PubMedGoogle Scholar
  124. 124.
    Porter SE, Greenwell PW, Ritchie KB, Petes TD. The DNA-binding protein Hdf1p (a putative Ku homologue) is required for maintaining normal telomere length in Saccharomyces cerevisiae. Nucleic Acids Res 1996;24:582–5.PubMedGoogle Scholar
  125. 125.
    Hsu HL, Gilley D, Blackburn EH, Chen DJ. Ku is associated with the telomere in mammals. Proc Natl Acad Sci USA 1999;96:12454–8.PubMedGoogle Scholar
  126. 126.
    Gravel S, Larrivee M, Labrecque P, Wellinger RJ. Yeast Ku as a regulator of chromosomal DNA end structure. Science 1998;280:741–4.PubMedGoogle Scholar
  127. 127.
    Gasser SM. A sense of the end. Science 2000;288:1377–9.PubMedGoogle Scholar
  128. 128.
    Mimori T, Hardin JA, Steitz JA. Characterization of the DNA-binding protein antigen Ku recognized by autoantibodies from patients with rheumatic disorders. J Biol Chem 1986;261:2274–8.PubMedGoogle Scholar
  129. 129.
    Paillard S, Strauss F. Analysis of the mechanism of interaction of simian Ku protein with DNA. Nucleic Acids Res 1991;19:5619–24.PubMedGoogle Scholar
  130. 130.
    Cary RB, Peterson SR, Wang J, Bear DG, Bradbury EM, Chen DJ. DNA looping by Ku and the DNA-dependent protein kinase. Proc Natl Acad Sci USA 1997;94:4267–72.PubMedGoogle Scholar
  131. 131.
    Dynan WS, Yoo S. Interaction of Ku protein and DNA-dependent protein kinase catalytic subunit with nucleic acids. Nucleic Acids Res 1998;26:1551–9.PubMedGoogle Scholar
  132. 132.
    Bailey SM, Meyne J, Chen DJ, et al. DNA double-strand break repair proteins are required to cap the ends of mammalian chromosomes. Proc Natl Acad Sci U S A 1999;96:14899–904.PubMedGoogle Scholar
  133. 133.
    Lombard DB, Guarente L. Nijmegen breakage syndrome disease protein and MRE11 at PML nuclear bodies and meiotic telomeres. Cancer Res 2000;60:2331–4.PubMedGoogle Scholar
  134. 134.
    Nakamura TM, Moser BA, Russell P. Telomere binding of checkpoint sensor and DNA repair proteins contributes to maintenance of functional fission yeast telomeres. Genetics 2002;161:1437–52.PubMedGoogle Scholar
  135. 135.
    Takata H, Tanaka Y, Matsuura A. Late S phase-specific recruitment of Mre11 complex triggers hierarchical assembly of telomere replication proteins in Saccharomyces cerevisiae. Mol Cell 2005;17:573–83.PubMedGoogle Scholar
  136. 136.
    Jazayeri A, Falck J, Lukas C, et al. ATM- and cell cycle-dependent regulation of ATR in response to DNA double-strand breaks. Nat Cell Biol 2006;8:37–45.PubMedGoogle Scholar
  137. 137.
    Larrivee M, LeBel C, Wellinger RJ. The generation of proper constitutive G-tails on yeast telomeres is dependent on the MRX complex. Genes Dev 2004;18:1391–6.PubMedGoogle Scholar
  138. 138.
    Chan TA, Hermeking H, Lengauer C, Kinzler KW, Vogelstein B. 14-3-3Sigma is required to prevent mitotic catastrophe after DNA damage. Nature 1999;401:616–20.PubMedGoogle Scholar
  139. 139.
    Xing H, Kornfeld K, Muslin AJ. The protein kinase KSR interacts with 14-3-3 protein and Raf. Curr Biol 1997;7:294–300.PubMedGoogle Scholar
  140. 140.
    Dhar S, Squire JA, Hande MP, Wellinger RJ, Pandita TK. Inactivation of 14-3-3sigma influences telomere behavior and ionizing radiation-induced chromosomal instability. Mol Cell Biol 2000;20:7764–72.PubMedGoogle Scholar
  141. 141.
    Li Y, Kirschmann DA, Wallrath LL. Does heterochromatin protein 1 always follow code? Proc Natl Acad Sci USA 2002;99 Suppl 4:16462–9.PubMedGoogle Scholar
  142. 142.
    Singh PB, Miller JR, Pearce J, et al. A sequence motif found in a Drosophila heterochromatin protein is conserved in animals and plants. Nucleic Acids Res 1991;19:789–94.PubMedGoogle Scholar
  143. 143.
    Jones DO, Cowell IG, Singh PB. Mammalian chromodomain proteins: their role in genome organisation and expression. Bioessays 2000;22:124–37.PubMedGoogle Scholar
  144. 144.
    Eissenberg JC, Elgin SC. The HP1 protein family: getting a grip on chromatin. Curr Opin Genet Dev 2000;10:204–10.PubMedGoogle Scholar
  145. 145.
    Wreggett KA, Hill F, James PS, Hutchings A, Butcher GW, Singh PB. A mammalian homologue of Drosophila heterochromatin protein 1 (HP1) is a component of constitutive heterochromatin. Cytogenet Cell Genet 1994;66:99–103.PubMedGoogle Scholar
  146. 146.
    Saunders WS, Chue C, Goebl M, et al. Molecular cloning of a human homologue of Drosophila heterochromatin protein HP1 using anti-centromere autoantibodies with anti-chromo specificity. J Cell Sci 1993 ;104 (Pt 2):573–82.PubMedGoogle Scholar
  147. 147.
    Sharma GG, Hwang KK, Pandita RK, et al. Human heterochromatin protein 1 isoforms HP1(Hsalpha) and HP1(Hsbeta) interfere with hTERT-telomere interactions and correlate with changes in cell growth and response to ionizing radiation. Mol Cell Biol 2003;23:8363–76.PubMedGoogle Scholar
  148. 148.
    Ziv Y, Bielopolski D, Galanty Y, et al. Chromatin relaxation in response to DNA double-strand breaks is modulated by a novel ATM- and KAP-1 dependent pathway. Nat Cell Biol 2006;8:870–6.PubMedGoogle Scholar
  149. 149.
    Lechner MS, Levitan I, Dressler GR. PTIP, a novel BRCT domain-containing protein interacts with Pax2 and is associated with active chromatin. Nucleic Acids Res 2000;28:2741–51.PubMedGoogle Scholar
  150. 150.
    Schultz DC, Ayyanathan K, Negorev D, Maul GG, Rauscher FJ, 3rd. SETDB1: a novel KAP-1-associated histone H3, lysine 9-specific methyltransferase that contributes to HP1-mediated silencing of euchromatic genes by KRAB zinc-finger proteins. Genes Dev 2002;16:919–32.PubMedGoogle Scholar
  151. 151.
    Ayoub N, Jeyasekharan AD, Bernal JA, Venkitaraman AR. HP1-beta mobilization promotes chromatin changes that initiate the DNA damage response. Nature 2008;453:682–6.PubMedGoogle Scholar
  152. 152.
    Aucott R, Bullwinkel J, Yu Y, et al. HP1-{beta} is required for development of the cerebral neocortex and neuromuscular junctions. J Cell Biol 2008;183:597–606.PubMedGoogle Scholar
  153. 153.
    Vaquero A, Loyola A, Reinberg D. The constantly changing face of chromatin. Sci Aging Knowledge Environ 2003;2003:RE4.PubMedGoogle Scholar
  154. 154.
    Shogren-Knaak M, Ishii H, Sun JM, Pazin MJ, Davie JR, Peterson CL. Histone H4-K16 acetylation controls chromatin structure and protein interactions. Science 2006;311:844–7.PubMedGoogle Scholar
  155. 155.
    Gupta A, Sharma, G.G., Young, C.S.H., Agarwal, M.,Smith, E.R., Paull, T.T., Lucchesi, J.C., Khanna, K.K., Ludwig, T., and Pandita, T.K.,. Involvement of human MOF in ATM function. Mol Cell Biol 2005;25:5292–305.PubMedGoogle Scholar
  156. 156.
    Kusch T, Florens L, Macdonald WH, et al. Acetylation by Tip60 is required for selective histone variant exchange at DNA lesions. Science 2004;306:2084–7.PubMedGoogle Scholar
  157. 157.
    Thiriet C, Hayes JJ. Chromatin in need of a fix: phosphorylation of H2AX connects chromatin to DNA repair. Mol Cell 2005;18:617–22.PubMedGoogle Scholar
  158. 158.
    Sharma GG, Hall EJ, Dhar S, Gupta A, Rao PH, Pandita TK. Telomere stability correlates with longevity of human beings exposed to ionizing radiations. Oncol Rep 2003;10:1733–6.PubMedGoogle Scholar
  159. 159.
    Downs JA, Nussenzweig MC, Nussenzweig A. Chromatin dynamics and the preservation of genetic information. Nature 2007;447:951–8.PubMedGoogle Scholar
  160. 160.
    Mailand N, Bekker-Jensen S, Faustrup H, et al. RNF8 ubiquitylates histones at DNA double-strand breaks and promotes assembly of repair proteins. Cell 2007;131:887–900.PubMedGoogle Scholar
  161. 161.
    Scott SP, Pandita TK. The cellular control of DNA double-strand breaks. J Cell Biochem 2006;99:1463–1475.Google Scholar
  162. 162.
    Hunt CR, Pandita RK, Laszlo A, et al. Hyperthermia activates a subset of ataxia-telangiectasia mutated effectors independent of DNA strand breaks and heat shock protein 70 status. Cancer Res 2007;67:3010–7.PubMedGoogle Scholar
  163. 163.
    Agarwal M, Pandita S, Hunt CR, et al. Inhibition of telomerase activity enhances hyperthermia-mediated radiosensitization. Cancer Res 2008;68:3370–8.PubMedGoogle Scholar
  164. 164.
    Pandita TK, Richardson, C. Chromatin remodling finds its place in the DNA double-strand break response. Nucleic Acids Res 2009 (online).Google Scholar
  165. 165.
    Misri S, Pandita S, Kumar R and Pandita TK. Telomeres, histone code and DNA damage. Cytogenetics Genome Res. 2008;122:297–307.Google Scholar

Copyright information

© Springer Science+Business Media B.V. 2009

Authors and Affiliations

  1. 1.Department of Radiation OncologyWashington University School of MedicineSt LouisUSA

Personalised recommendations